Leukocyte function-associated antigen (LFA-1, alphaLbeta2, CD11a/CD18) is an integrin-type cell adhesion molecule that is predominantly involved in leukocyte trafficking and extravasation. LFA-1 is expressed on leukocytes and interacts with ligands ICAM-1, ICAM-2 and ICAM-3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune system.
ICAM-1 (CD54) is a cell surface adhesion receptor that is a member of the immunoglobulin protein super-family. ICAM-1 is expressed on a variety of hematopoietic and non-hematopoietic cells and is unpregulated at sites of inflammation by a variety of inflammatory mediators.
The LFA-1/ICAM-1 interaction is known to be al least partially responsible for lymphocyte adhesion, monocyte adhesion, and neutrophil adhesion to endothelial cells.
LFA-1 is also frequently expressed on hematopoietic and solid cancer cell types. In these cases, LFA-1 plays an integral role in the mechanisms of cancer cell adhesion, growth, invasion, and metastasis and has been shown to influence the immune response to malignant cells. On the other hand, a circulating form of ICAM-1 has been found in increased levels in patients with cancer that in turn promotes angiogenesis and altered cancer cell behavior.
The structure of LFA-1 includes distinct intracellular and extracellular domains that are believed to participate and/or regulate ICAM binding. LFA-1 binds to ICAM-1 located on neighboring endothelial cells by a particular fragment called the Inserted domain (I-domain). This domain is found in all beta2 integrins, as well as in many other proteins. Within the I-domain of LFA-1 (and other proteins) there is a single metal ion dependent adhesion site (MIDAS) that preferentially binds divalent cations. Binding of either cation is required for ligand interaction and is believed to induce the conformational changes in LFA-1 necessary for binding. Cation binding may therefore be a regulatory mechanism that responds to changes in the extracellular leukocyte environment.
The LFA-1/ICAM-1 interaction has been associated with several important disease processes such as cancer metastasis from gastrointestinal carcinoma, melanoma and lymphoma, as well as inflammatory and autoimmune diseases. There is a need to find novel compounds capable of inhibiting LFA-1/ICAM-1 interaction. More particularly, there is a need to find effective therapeutic agents for those disorders/diseases whose pathogenic and pathophysiological mechanisms are mediated by LFA-1/ICAM-1 interaction.
Several compounds derived from chiral nitroprolines structurally similar to the ones disclosed in the present invention, capable of inhibiting the structure of the N-terminal extracellular domain of the alpha-4 subunit of VLA-4, were described in Spanish patent application ES2216712, however none of these compounds is capable of inhibiting LFA-1/ICAM-1 interaction.
The structure of the N-terminal extracellular domain of the alpha-4 subunit of VLA-4 consists of a seven four-stranded beta-sheets propeller that does not contain any inserted domain (Springer T. A. Proc. Natl. Acad. Sci. USA 1997, 94, 65). In contrast, the N-terminal extracellular domain of the alpha-L subunit of LFA-1 has an inserted domain that includes a metal ion-depending adhesion site (MIDAS) whose structure has been resolved (Shimaoka, M. et al. Cell 2003, 112, 99).